NEPRO – Cartilage-Hair Hypoplasia

This summary outlines the association between NEPRO (HGNC:24496) and cartilage-hair hypoplasia (MONDO_0009595). The reported cases demonstrate an autosomal recessive inheritance pattern with biallelic variants in NEPRO. Affected individuals present with a characteristic constellation of skeletal dysplasia, including severe short stature, brachydactyly, cutis laxa, joint hypermobility, joint dislocations, short metacarpals, and metaphyseal irregularities. The clinical presentation is consistent across independent families, supporting the association with this ribosomopathy. These features are critical for diagnostic decision-making and further research into the molecular basis of the disease. The presented evidence is drawn from recently published case studies and supports a targeted approach to clinical testing (PMID:31250547).

Genetic evidence stems from a comprehensive analysis involving a 6‐year‐old proband identified through trio exome sequencing and two additional families comprising four affected individuals. In all cases, the affected patients harbored biallelic variants in NEPRO, reinforcing the autosomal recessive pattern of inheritance. Segregation analysis within these families supports the co-segregation of the variant with the disease phenotype. The consistency of the phenotype across these cases further substantiates the genetic contribution of NEPRO in cartilage-hair hypoplasia. Each affected individual displays overlapping and distinctive clinical markers that guide both clinical evaluation and genetic counseling (PMID:31250547).

The reported variant, c.435G>C (p.Leu145Phe), is identified in multiple unrelated families and is the first-line candidate for the gene-disease association. This variant is located in a conserved domain of the protein where similar missense changes have been implicated in decreased protein stability. Its presence in homozygous state in the affected individuals confirms its pathogenic nature. Detailed protein modeling and stability prediction analyses reveal that the mutant NEPRO protein has reduced stability, providing a mechanistic insight into the functional impairment. Such converging genetic evidences, when combined with the observed phenotype, enhance the confidence in the pathogenicity of this variant (PMID:31250547).

Functional assessments include computational protein modeling and stability predictions which indicate decreased stability of the mutant NEPRO protein. Although in vitro or in vivo validation studies are pending, these functional data serve as supportive evidence for the underlying pathogenic mechanism. The predicted impact on the protein’s structure aligns with the clinical findings observed in all affected individuals. The experimental insights, although limited in scope, provide an important link between the genetic variant and the clinical phenotype. Such functional evidence, when integrated with segregation and case report data, strengthens the overall disease association. This synergy between genetic and functional data is crucial for comprehensive diagnostic evaluations (PMID:31250547).

In summary, the integration of genetic findings, segregation data, and in silico functional assessments supports a moderate to strong association between biallelic variants in NEPRO and cartilage-hair hypoplasia. The recurrent observation of the c.435G>C (p.Leu145Phe) variant in affected individuals across independent families, in conjunction with consistent clinical features, provides a reliable basis for diagnosis and further exploration. Pending additional functional studies, the current evidence already offers substantial support for incorporating NEPRO testing in diagnostic workflows for patients with compatible skeletal dysplasias. Key take-home: NEPRO should be considered in the genetic evaluation of patients presenting with cartilage-hair hypoplasia due to the robust and consistent evidence linking its biallelic variants to the disease phenotype.

References

• American journal of medical genetics. Part A • 2019 • An emerging ribosomopathy affecting the skeleton due to biallelic variations in NEPRO. PMID:31250547

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